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Antiviral target compound profile for pandemic preparedness

Enhancing safety in surface mine blasting operations with IoT based ground vibration monitoring and prediction system integrated with machine learning

mTOR signaling controls protein aggregation during heat stress and cellular aging in a translation- and Hsf1-independent manner

The expand indication of HER2 targeted therapies by monitoring of circulating tumor cells.

482 Background: Despite success in the HER2 targeted therapies for metastatic gastric cancer patients, the conventional assessment of HER2 status in tumor tissue specimens is still under debate. Methods: On-chip sorting system was used for the isolation of circulating tumor cells (CTCs). The fluorescence signal intensity > 50 is set to be a threshold value for distinguishing between positive and negative HER2 on CTCs. Epithelial mesenchymal transition (EMT) was assessed by the vimentin and cytokeratin. DNA was extracted from CTCs and applied to the cancer gene panel. Results: In 27 patients with metastatic gastric cancer, 13 patients showed HER2 positive in tumor tissues (Group A) who were treated with cytotoxic agents and HER2-targeted therapy while 14 patients exhibited negative and treated with cytotoxic agents. In these 14 patients, 8 patients showed HER2 positive (Group B) and 6 patients displayed HER2 negative (Group C) on CTCs. HER2 expression on CTCs was associated with EMT (p<0.001). Increased expression of EMT was seen in Group A and B, indicating they are likely to have metastasis. Group B exhibited worse PFS than others (13.8 M in A, 7.0 M in B and not reached in C, p=0.012). In addition, genomic analysis identified cancer gene mutations, some of which were involved in mechanisms underlying EMT and were shared between Group A and B. Considering HER2 expression on CTCs in Group B, an additional HER2-targeted therapy may be beneficial. Conclusions: Our study suggests that monitoring of circulating tumor cells leads to the expand indication of the HER2 targeted therapies in patients with metastatic gastric cancer.

Risk factors for relapse based on the molecular profiling of Japanese patients with stage II colorectal cancer.

215 Background: The association between the molecular profiles and prognosis of Stage II colorectal cancer (CRC) remains unclear. This study aimed to evaluate the long-term outcomes of Stage II CRC based on the molecular profiling and to examine the risk factors for relapse. Methods: We retrospectively enrolled Japanese patients with pStage II CRC without pre- and/or postoperative adjuvant therapy and whose surgically resected specimens were evaluated using gene expression and whole exome analyses from January 2014 to December 2018. We evaluated the 5-year overall survival (OS) and relapse-free survival (RFS), and examined the risk factors for RFS. Results: We evaluated 322 patients with pStage II CRC, including 126 (39.1%) with right colon cancer, 133 (41.3%) with left colon cancer and 63 (19.6%) with rectal cancer. There were 87 patients (27.0%) with pT4, 175 (54.3%) with venous invasion, 120 (37.3%) with lymphatic invasion, and 68 (21.1%) with perineural invasion. Whole exome analyses revealed that there were 48 patients (14.9%) with MSI-High, and the presence of mutations in key genes for colorectal cancer development was as follows: APC , 245 (76.1%); TP53 , 208 (64.6%); KRAS , 134 (6.5%); PIK3CA , 64 (19.9%); FBXW7 , 27 (8.4%); and BRAF , 21 (6.5%). The 5-year OS and RFS rates were 98.0% and 90.7%, respectively. According to the consensus molecular subtype (CMS) classification based on gene expression, 76 patients (23.6%) had CMS4 and a significantly lower RFS than the other patients (5-year RFS: 83.8% vs. 92.9%, p=0.017). The independent risk factors for RFS were perineural invasion (Hazard ratio [HR] 5.316, p<0.001) and CMS4 (HR 2.399, p=0.020). Conclusions: Molecular profiling of Stage II CRC to assess the risk factors for relapse may contribute to the indication and drug selection for postoperative adjuvant chemotherapy and lead to personalized treatment to improve prognosis.

A single institution retrospective study evaluating mitomycin dosing during chemoradiation in anal squamous cell carcinoma.

7 Background: Mitomycin (MMC) is used concurrently during chemoradiation (CRT) treatment for non-metastatic anal squamous cell carcinoma (SCCA). The most effective dosing of MMC is not established, and due to concerns for tolerability, many have adopted a dose-reduction strategy. This study evaluates differences in treatment response and recurrence between MMC dosing in this setting. Methods: Demographics, age, smoking history, staging, and treatment history were collected for patients with non-metastatic SCCA treated with CRT from January 2011-September 2024 at a tertiary cancer center. Chi-square analyses compared categorical variables, and ANOVA tests were used to compare treatment response and recurrence between 3 MMC doses (12mg/m 2 x 1 dose with cap of 20mg, 10mg/m 2 x 2 doses, 10mg/m 2 x 1 dose). Results: There were 124 patients, 6 of whom were excluded due to lack of follow up. Of the 118 included, 70% were female, 16% Black, 3% Hispanic/Latino, and 58% current/former smokers. Median age was 61 years (31-98). Thirty-three (28%) pts were treated with MMC 12mg/m 2 , 71 (60%) with 10mg/m 2 x2 doses, and 14 (12%) with 10mg/m 2 x1 dose. Stage I included 18% of 12mg/m2, 7% of 10mg/m 2 x2 doses, and 7% of 10mg/m 2 x1 dose; stage II included 18% of 12mg/m2, 37% of 10mg/m 2 x2 doses, and 50% of 10mg/m 2 x1 dose; stage III included 64% of 12mg/m2, 56% of 10mg/m 2 x2 doses, and 43% of 10mg/m 2 x1 dose. A total of 39.7% were treated with MMC/capecitabine and 60.3% with MMC/fluorouracil. Complete response was achieved in 91% receiving the 12mg/m 2 , 75% receiving 10mg/m 2 x2 dose, and 71% receiving 10mg/m 2 x1 dose (p=0.13, Table 1). Using logistic regression with MMC dose, stage, age, and smoking status as independent predictors, the odds of achieving complete response were lower in 10mg/m 2 x2 doses (p=0.03) and 10mg/m 2 x1 dose (p=0.03) compared to 12mg/m 2 . Local, regional, or metastatic recurrence occurred in 15% of pts receiving 12mg/m 2 , 17% of 10mg/m 2 x2 doses, and 7% of 10mg/m 2 x1 dose. No significant difference was seen in local (p=0.52), regional (p=0.93), metastatic (p=0.87), or overall recurrence (p=0.65) between the MMC doses. Conclusions: Odds of achieving complete response was greater with 12mg/m 2 dosing. Local, regional, and metastatic recurrence were similar among the different MMC dosing cohorts. Differences in tolerance and side effects should be delineated to guide individualized dosing of MMC.

Nutritional and anti-nutritional evaluation of injera made from Sorghum, Rice, Teff, and Flaxseed flours using D-optimal mixture design

Histone N-tails modulate sequence-specific positioning of nucleosomes

Optimal cut-off value for lymph node harvesting in colon cancer based on tumor stage and sidedness: A retrospective analysis of a Japanese nationwide cohort.

149 Background: The presence of fewer than 12 harvested lymph nodes (LN) is currently considered a risk factor in stage II colon cancer (CC). However, this cut-off value does not take into consideration the biological differences associated with tumor sidedness. Moreover, the applicability of this cut-off value to stage III CC is unknown. Methods: Patients with pathological stage II/III CC who underwent curative surgical resection were assessed using data from the Japanese Society for Cancer of the Colon and Rectum database (2001–2015). The optimal cut-off value of harvested LN was evaluated by analyzing all cut-off values (i.e., 3–40), taking into account the point estimate of the hazard ratio (HR) and lower limit of the 95% confidence interval (CI), according to the tumor stage (II/III) and sidedness (right/left). A Cox proportional hazards model was used to investigate the impact of the number of harvested LN on overall survival, adjusting for age, sex, T stage, histology, size of tumor, sidedness, adjuvant chemotherapy and extent of colon resection. Multivariate analysis was also conducted. Results: From the data, 4249 (left/right; 3248/1001) and 3549 (left/right; 2798/751) patients with stage II and III CC, respectively, were identified. The median number of harvested LN was identical between stage II (18, interquartile range [IQR] (12–15)) and III (18, IQR (13–25)). However, this number was higher in right-sided CC (21, IQR (14–31)) versus left-sided CC (17, IQR (12–24)). In stage II, the conventional cut-off value (i.e., 12 LN) was identified as a prognostic factor in the multivariate analysis (HR 1.45; 95% CI: 1.20–1.75; p<0.001). Nevertheless, the prognostic impact of the number of harvested LN was stronger when the optimal cut-off value was set to 7 (HR 1.88; 95% CI: 1.44–2.44; p<0.001). In stage III, the optimal cut-off value was 12 (HR 1.88; 95% CI: 1.44–2.44; p<0.001). When evaluated based on tumor sidedness, the optimal cut-off value differed, especially for stage III. Data are shown in the table. Similar results were obtained following the exclusion of the extent of bowel resection as variable in Multivariate analysis. Conclusions: While the presence of 12 harvested LNs remains a valid prognostic factor, the optimal cut-off value can be further evaluated based on tumor stage and sidedness. Stage II Stage III All Left Right All Left Right Cut-off value 12 12 12 12 12 12 N(>cut-off/<cut-off) 3209/1040 2371/877 838/163 2814/735 2181/617 633/118 HR(>cut-off/<cut-off)(95% CI) 1.45 (1.20-1.75) 1.49 (1.20-1.84) 1.31 (0.85-2.02) 1.30 (1.09-1.55) 1.27 (1.05-1.54) 1.43 (0.97-2.13) P value <0.001 <0.001 0.216 <0.003 0.015 0.073 Cut-off value 7 7 10 20 13 N(>cut-off/<cut off) 3930/319 2977/271 889/112 1200/1598 609/142 HR(>cut-off/<cut-off)(95% CI) 1.88 (1.44-2.44) 2.07 (1.56-2.74) 1.39 (0.84-2.27) 1.35 (1.13-1.60) 1.59 (1.11-2.28) P value <0.001 <0.001 0.198 <0.001 0.011

Care delivery and biomarker testing for people with colorectal cancer receiving 4R care sequence plans.

107 Background: The 4R Oncology model has shown improvements in patient knowledge of care and timing/sequence of key care events (1,2) but has not been studied in colorectal cancer specific. 4R is Right Info/Care/Patient/Time. The 4R Care Sequence is a patient-facing care plan describing the course and timing/sequence of care. Here we report the impact of using 4R for patients with colorectal cancer. Methods: We tested the impact of 4R care sequence plans on patient reported biomarker testing and care delivery referrals and receipt of services at a colorectal cancer program via patient surveys. 4R Plans were provided to patients from Sept ‘23 – Aug ’24 (4R cohort). Patient-reported data were analyzed to compare the 4R cohort (N = 19) to a control cohort of patients who received care pre-4R, Sept ‘22 – Aug ’23 (N = 60). Used Fisher’s exact test. Results: Response rates: 4R cohort 79% (19/24), Control cohort 87% (41/47). Comparing the 4R cohort to the control cohort respectively, patients were male (47%, 54%), White (89%, 76%), average age (57, 52), and reported income less than $30,000 (21%, 24%). The 4R cohort significantly improved care delivery in five metrics, and directionally improved in care delivery metrics compared to the control cohort (table). One biomarker testing metric significantly improved and other biomarker testing metrics directionally improved in the 4R cohort vs. the control cohort (Table). Conclusions: The use of 4R Care Sequence plans for patients with colorectal cancer facilitated improvements in care delivery and patient ‘s awareness of biomarker testing. While there were directional improvements in all metrics, there is opportunity and room for additional improvements. The team will continue to work on efforts to improve these metrics and optimize the use of 4R Care Sequence plans for patients with colorectal cancer. 1. Trosman 2021. 2. Liu 2023. Referral and receipt of services, biomarker testing. 4R chortN=19 Control cohort N=41 Pvalue Did your provider recommend you see a nutritionist/dietitian? 89% 20% 0.0001 If Yes, did you see a nutritionist/dietitian ? 84% 20% 0.001 Did your provider recommend you see your primary care physician about staying as healthy as possible during care treatment? 95% 29% 0.0001 If Yes, did you see your primary care physician? 95% 67% 0.04 Did your provider recommend you get support for transportation, food, housing, insurance, or other needs? 42% 12% 0.01 If Yes, did you get support for these needs? 88% 67% 0.4 Did you provider recommend you get help for emotional distress or worry? 53% 46% 0.4 If Yes, did you get help for emotional distress or worry? 70% 47% 0.2 Did your care providers talk to you about biomarker testing after your cancer diagnosis? 53% 37% 0.2 If yes, how clear was it to you why biomarker testing was or was not recommended for you? 90% 73% 0.3 Did you get biomarker testing? 63% 34% 0.03 Did your care providers discuss results of biomarker tests with you? 92% 87% 0.6

Use of nucleotyping and tumor stroma ratio to predict prognosis in patients with resected intestinal-type gastric cancer.

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.

Comprehensive analysis reveals the tumor suppressor role of macrophage signature gene FCER1G in hepatocellular carcinoma

Discovery of a tribenzophenazine analog for binding to the KRAS mRNA G-quadruplex structures in the cisplatin-resistant non–small cell lung cancer

Bragg peak proton irradiation and ATM inhibition for rectal cancer.

259 Background: Rectal cancer patients with a complete response (CR) after chemotherapy and radiotherapy may opt for non-operative management. Currently only 20-40% of patients reach a CR. Escalating the dose of radiation may increase the risk of toxicity. ATM inhibitors (ATMi) are potent radiosensitizers in colorectal cancer (CRC). Proton irradiation exhibits an entrance portion of the beam (ENT) where dose is deposited sparsely and a Bragg Peak (BP) with virtually no ‘exit dose’ thereafter. ATMi renders cells uniquely hypersensitive to proton BP, and BP+ATMi may increase the response of Mismatch Repair proficient (pMMR) rectal cancer to immunotherapy. Methods: Tumor efficacy and immunogenicity was assessed using clonogenic survival, γH2AX foci, micronuclei, and cytoplasmic cGas assays after indicated IR modalities +/-ATMi. Normal tissue toxicity was assessed via murine models of non-tumor bearing BALB/c after whole-abdominal irradiation (WAI) after indicated IR modalities +/- ATMi via acute weight loss, FITC/Dextran assay, and Radiation Injury Score (RIS, Scale 0-18) in jejunal and rectal samples at 4 days post-IR. Results: ATMi decreased clonogenic survival across all types of radiation, but the effect was most pronounced with BP protons. BP+ATMi also significantly increased unresolved γH2AX foci, micronuclei, and cytoplasmic cGas compared to ENT+ATMi. Normal tissue toxicity studies demonstrated that BP+ATMi did not significantly increase acute weight loss, RIS in jejunal or rectal tissue; but did increase FITC/Dextran intestinal permeability. Conclusions: Inhibition of ATM preferentially radiosensitized BP protons compared to x-rays or ENT protons in CRC but not in normal tissue based on weight loss and histopathological evaluation. Differential tumor efficacy and normal tissue toxicity after x-ray, entrance and Bragg Peak Protons +/- ATM inhibitor. A B C D E F G H I J DMSO 1 1 1 2.9 1.5 8764 96.4 10 0.3 0.2 ATMi 0.873 0.842 0.723 8.2 3.0 16300 98.5 5.8 0.7 0.8 x-ray 0.615 0.751 0.109 82.4 6.2 4.8 1.0 x-ray+ATMi 0.123 0.344 0.011 80.0 14.4 5.2 1.5 ENT protons 0.293 0.515 0.080 10.2 5.8 10429 78.5 6 2.9 1.5 ENT+ATMi 0.091 0.066 0.013 15.1 7.2 12274 73.0 23.8 5.2 3.8 BP protons 0.213 0.340 0.032 12.0 12.6 7192 75.6 24.6 4.1 3.7 BP+ATMi 0.074 0.038 0.004 22.7 16.2 43677 73.6 310.4 5.3 4.3 Clonogenic survival of pMMR colorectal cancer cell lines after IR (4 Gy) +/- 10nM AZD1390 (ATM inhibitor) ofA) HT29, B) CT26, and C) SW480 cell lines. D) γH2AX foci at 24 hours post-IR in HT29. E) Micronuclei, and F) cytoplasmic cGas integrated density per cell via immunofluorescence in SW480 72 hours post-IR. WAI (10Gy/1 fraction) was delivered to non-tumor bearing BALB/c mice which were followed for G) acute weight loss (% from baseline), and H) FITC/Dextran permeability assay. Tissue samples were graded for Radiation Injury Score in I) jejunal, and J) rectal samples at 4 days post-IR (n=5 per cohort, 3 samples per mouse). Figures are means of triplicate data.

First-in-human phase 1/2 study (MYCHELANGELO I) of first-in-class epigenomic controller OTX-2002 targeting MYC oncogene in patients with hepatocellular carcinoma (HCC) and other solid tumors.

606 Background: The c-MYC (MYC) oncogene is a master transcription factor of tumor cell and microenvironment regulation; it is often dysregulated in cancer, including HCC. OTX-2002 is a MYC-targeted Epigenomic Controller (MYC-EC), an mRNA drug substance encapsulated in a clinical lipid nanoparticle (LNP), designed to downregulate MYC expression pre-transcriptionally with high specificity and durability, inhibiting tumor cell viability while sparing normal cells. Methods: A first-in-human dose-escalation study (NCT05497453) investigates OTX-2002 monotherapy in HCC and other solid tumors. Key outcomes include safety, tolerability, pharmacokinetics (PK) and the recommended dose for expansion. In addition to standard safety measures, LNP-associated safety measures including cytokine profiling and an assessment of the presence of anti-PEG antibodies (ADA) were included. Initial pharmacodynamic activity (PD) was assessed via measurement of DNA methylation at the MYC locus in cell-free DNA [cfDNA] from whole blood. Results: As of August 23, 2024, 24 patients were treated at 6 doses (19 HCC, 1 colorectal, 1 cervical, 1 pancreatic, 2 sarcoma). OTX-2002 was generally well-tolerated; most adverse events (89%) were low grade, with infusion-related reactions being the most common (30%). Consistent with known LNP profiles, OTX-2002 adverse events were transient and manageable, including cytokine and ADA expression levels. Plasma PK exposures of OTX-2002 were linear across the first five doses analyzed. Significant, on-target dose-dependent changes in MYC gene methylation were seen in cfDNA for all patients post-dose and were durable for at least 15 days, consistent with the designed durability of the MYC-EC. Updated data will be presented. Conclusions: OTX-2002 is well-tolerated and induces rapid and durable epigenomic changes to the MYC locus. These results provide clinical proof of mechanism of the epigenomic controller platform and support continued development of OTX-2002. Clinical trial information: NCT05497453 .

Effect of tRF-28-ZJ47D112Z4DZ on the pathogenesis of gastric cancer through targeting cyclin D1/CDK4 and its early diagnostic value.

475 Background: Gastric cancer exhibits high incidence and mortality rates worldwide. Current research on gastric cancer aims to discover stable and effective early diagnostic markers, as well as uncover the disease's pathogenesis. tRNA-derived fragment (tRF) is a newly discovered regulatory non-coding RNA, which plays an important role in tumor diagnosis and treatment. Methods: This study, through transcriptome sequencing and MINTBase v2.0 database, screened out a new molecule tRF-28-ZJ47D112Z4DZ (tRF-28) related to gastric cancer. An absolute quantitative method was established to quantify the level of tRF-28 in plasma. ROC curve, survival curve, Cox regression model were constructed, and clinicopathological factors were collected to analyze the diagnostic value of tRF-28. "Overexpression" and "knockdown" tRF-28 gastric cancer cell models and xenograft tumor models were established to study the effects of tRF-28 on cell proliferation. Using bioinformatics, qRT-PCR, Western blot, dual luciferase reporter gene, fluorescence in situ hybridization, RNA binding protein immunoprecipitation assay, rescue experiment and immunohistochemistry to study the regulatory role of tRF-28 by binding to the 3'UTR of CCND1. Results: This study clarified the tRF-28 levels in the plasma of healthy individuals, and gastric benign and malignant lesions, providing a new candidate biomarker for the early diagnosis of gastric cancer. Through upregulating and downregulating the level of tRF-28 in gastric cancer cells, it was revealed that tRF-28 inhibits the proliferation of gastric cancer cells in vivo and in vitro by regulating key proteins such as Cyclin D1, CDK4, Rb, and p-Rb. In studying specific molecular mechanisms, tRF-28 and CCND1 were co-located in the cytoplasm. tRF-28 combines with Ago2 protein to form a complex and plays a role in silencing the target gene CCND1 in the cytoplasm. The rescue experiments revealed that silencing the target gene CCND1 can reverse the carcinogenesis effect of tRF-28 inhibitors, clarifying the biological functions of tRF-28 by regulating CCND1. Conclusions: Based on a series of research findings, we elucidated that tRF-28 form a complex with Ago2 protein, binding to the 3' UTR of CCND1 to downregulate Cyclin D1, CDK4, and other critical proteins, thereby inhibiting the proliferation of gastric cancer cells. Our study aims to offer new insights into identifying potential early diagnostic markers and therapeutic targets for gastric cancer.

Exploring potential biomarkers for acute myocardial infarction by combining circadian rhythm gene expression and immune cell infiltration

Abstract Current diagnostic biomarkers for acute myocardial infarction (AMI), such as troponins, often lack specificity, leading to false positives under non-cardiac conditions. Recent studies have implicated circadian rhythm and immune infiltration in the pathogenesis of AMI. This study hypothesizes that analyzing the interplay between circadian rhythm-related gene expression and immune infiltration identify highly specific diagnostic biomarkers for AMI. Our results demonstrated differential expression of 15 circadian rhythm-related genes (CRGs) between AMI patients and healthy individuals, with five key genes—JUN, NAMPT, S100A8, SERPINA1, and VCAN identified as key contributors to this process. Functional enrichment analyses suggest these genes significantly influence cytokine and chemokine production in immune responses. Immune infiltration assessments using ssGSEA indicated elevated levels of neutrophils, macrophages, and eosinophils in AMI patients. Additionally, we identified potential therapeutic implications with 13 pivotal miRNAs and 10 candidate drugs targeting these genes. The Benjamini–Hochberg method was employed to adjust for multiple testing, and the results retained statistical significance. RT-qPCR analysis further confirmed the upregulation of these five genes under hypoxic conditions, compared to controls. Collectively, our findings highlight the critical role of CRGs in AMI, providing a foundation for improved diagnostic approaches and novel therapeutic targets.

Human microRNA miR-197-3p positively regulates HIV-1 virion infectivity through its target DDX52 by stabilizing Vif protein expression

Rate of gene fusion/rearrangement identification in GI cancers as sequencing evolved from limited panels to whole exome sequencing.

809 Background: Gene fusion/rearrangements occur at a frequency of 0-15% in GI system cancers. Detection and treatment of fusion genes such as NTRK, FGFR2, NRG1 and RET fusions are included in NCCN guidelines and are commonly detected using next generation sequencing (NGS). NGS panels have continued to expand over time, which should result in increases in the identification of gene fusions. The aims of this study were to describe the percent of patients with advanced GI tumors undergoing NGS with identified gene rearrangements across time as panels expanded. Methods: The study included 7237 patients in the Kaiser Permanente Northern California Integrated Health System receiving care for advanced GI cancers from 2017 to Aug 2024, whose tumors samples were evaluated using NGS (Stomach=926, Colorectal=2792, Gallbladder=569, Esophagus=761, liver=218, Pancreas=1971). Results: A total of 231 patients (3.2%) were identified with a gene rearrangement, including 4.6% in stomach(N=43), 2.8% in colorectal(N=78), 8.9% in gallbladder(N=24), 5.3% in esophagus(N=40), and 1.9% in pancreatic (N=38 ). Rearrangements included NTRK1/2/3, FGFR2/3, NRG, ALK, ROS, CLDN18-ARHGAP, RSPO2/3, DNAJB1-PRKACA, BRAF, MET and RET. The numbers per year were (see table). Conclusions: The use of more comprehensive NGS panels such as WES did not appear to increase the detection rate for fusion/rearrangements. In resource limited settings, limited panels may suffice. The number of GI cancer patients getting NGS testing has increased over time. Gene rearrangements/fusions identified per year. YEAR 2018 2019 2020 2021 2022 2023 2024 (Jan – Aug) Gene Rearrangement identified 29 37 43 55 54 62 38 TOTAL GI Cancer Samples Sequenced 610 858 900 1047 1249 1181 785 Percentage 4.75% 4.31% 4.78% 5.25% 4.32% 5.25% 4.84%

Efficacy and safety of glecirasib (JAB-21822) monotherapy and in combination with cetuximab in patients with KRAS G12C-mutated advanced colorectal cancer.

191 Background: Glecirasib (JAB-21822), a highly selective, covalent and oral KRAS G12C inhibitor, has demonstrated a favorable safety profile and promising efficacy result as a monotherapy in NSCLC. We previously reported preliminary data of glecirasib monotherapy (NCT05009329) and in combination with cetuximab (NCT05194995) in KRAS G12C-mutated advanced Colorectal Cancer (CRC); here, we present the updated efficacy results. Methods: Patients (pts) with advanced CRC harboring KRAS G12C mutation were enrolled and treated with either single agent glecirasib (800mg QD) or glecirasib (800mg QD) combined with cetuximab. The primary endpoint was overall response rate (ORR). The secondary endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: As of June 30, 2024, 44 pts received glecirasib (median follow up was 21.9 months). The median age was 55.5 years with female (38.6%) /male (61.4%), ECOG PS 0 (25.0%) /1 (75.0.%), and 79.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 22.7% (10/44) and 86.4% (38/44), respectively. Median DoR was 4.4months (95%CI: 4.2, 9.7) , median PFS was 5.6 months (95%CI: 4.1, 7.0), and median OS was 16.0 months (95%CI: 8.8, 26.3). Any grade treatment-related adverse events (TRAEs) occurred in 41 (93.2%) pts, the most common ones (>20%) being anemia, blood bilirubin increased, hypertriglyceridemia and white blood cell count decreased. Grade 3-4 TRAEs occurred in 9 (20.5%) pts. No grade 5 TRAEs occurred. No patient discontinued treatment due to TRAEs. Among the47 pts treated with combination regimen (median follow up was 18.7 months), the median age was 54.8 years with female (53.2%)/ male (46.8%), ECOG PS 0 (44.7%) /1 (55.3%), and 74.5% having received ≥ 2 prior lines of therapy. The confirmed ORR and DCR were 50% (23/46) and 87.0% (40/46), respectively. Median DoR was 5.1 months (95%CI: 4.1, 6.9), median PFS was 6.9 months (95%CI: 5.4-6.9), and median OS was 19.3 months (95%CI: 13.1, NE). Any grade TRAEs occurred in 46 (97.9%) pts, the most common ones (>20%) being rash, skin fissures, blood bilirubin increased, ALT increased, AST increased, anemia and proteinuria. Grade 3-4 TRAEs occurred in 9 (19.1%) pts. No grade 5 TRAEs occurred. 2(4.3%) pts discontinued treatment due to TRAEs. Conclusions: Glecirasib in combination with cetuximab demonstrated better efficacy compared with glecirasib monotherapy in advanced KRAS G12C mutated advanced CRC, while maintaining a favorable safety profile. Clinical trial information: NCT05009329 , NCT05194995 .